Lithium is the most commonly used drug for the treatment of manic- depressive illness. The precise mechanisms underlying its clinical efficacy remain unknown. We have previously shown that long-term treatment of cerebellar granule cells (CGC) with relatively low doses of lithium increases the mRNA level of the immediate early gene product, c-Fos, and up-regulates the expression and function of m3-muscarinic receptors in these neurons. Since AP-1 and cAMP-responsive element (CRE) are key elements of transcriptional regulation for a variety of proteins with neurophysiological importance, we have investigated the effects of lithium on gene transcription in cultured CGC and in rats by measuring transcrtiption factor binding to AP-1 and CRE sites. We found that treatment of CGC with lithium chloride induces a concentration-dependent increase in AP-1 and CRE binding activities with maximal effects at 0.5-1.0 mM of this ion. Lithium's effects on AP-1 and CRE binding are biphasic within the first 24 hrs of treatment in immature CGC in culture and persistent in mature CGC, lasting as long as 7 days. These actions are concurrent with an increase in the mRNA levels of c-Fos and c-Jun as well as the protein levels of c-Fos, c-Jun and phosphorylated CRE binding protein (p-CREB). Gel supershift assays using transcription factor-specific antibodies revealed that p-CREB, Jun D and a Fos family protein(s) are components of the AP-1 binding complex in untreated and lithium-treated CGC. Chronic dietary treatment of rats with lithium carbonate for 4 weeks also significantly increases AP-1 and CRE binding activity in the frontal cortex, hippocampus, amygdala and cerebellum. Similar to the results obtained in CGC, p-CREB, Jun D and Fos family proteins are present in the AP-1 binding sites in the frontal cortex and hippocampus of untreated and lithium-treated rats. Our finding that lithium induces activation of transcription factor binding to AP-1 and CRE sites in vivo and in vitro provides a new avenue to study the mechanisms of action of lithium in the treatment of manic depressive illnes. In a parallel study, we explored the neuroprotective effects of lithium against neuro- excitatoxicity elicited by glutamate, a major excitatory amino acid neurotransmitter involved in the synaptic plasticity and pathogenesis of neurodegenerative and neuropsychiatric disorders. We found that long-term exposure to lithium chloride dramatically protects cultured rat CGC, cerebral cortical and hippocampal neurons against glutamate-induced excitotoxicity which involves apoptosis mediated by N-methyl-D-aspartate (NMDA) receptors. This neuroprotection occurs at therapeutically relevant concentrations (0.5-5.0 mM) with an EC50 of approximately 1.3 mM and requires treatment for 6-7 days for complete protection to occur, while a 24-hr treatment is ineffective. The protection is specific for glutamate-induced excitotoxicity and can be attributed to inhibition of NMDA receptor-mediated calcium influx measured by radiactive calcium uptake studies; the latter was confirmed by Fura-2 fluorescence microphotometry. The long-term effects of lithium are not due to down-regulation of NMDA receptor sites, nor are they related to its known ability to block inositol monophosphatase activity. Our results suggest that modulation of glutamate receptor hyperactivity represents, at least in part, the molecular mechanisms by which lithium alters brain function and exerts its clinical efficacy in the treatment for manic depressive illness. These novel actions of lithium also suggest that excessive glutamatergic neurotransmission may be the pathogenic mechanism underlying bipolar illness. In a related study, we found that lithium also robustly protects against carbamazepine and phenytoin-induced apoptosis and modestly inhibits age-induced death of CGC. However, unlike the protection against glutamate excitotoxicity, this effect of lithium on anticonvulsant-induced neurotoxicity does not require long-term treatment and occurs at relatively high concentrations (+/- 5 mM). The inhibition of carbamazepine neurotoxicity by lithium may have clinical implications, as combined treatment with lithium and carbamazepine is known to potentiate the effect of either drug alone in the treatment of manic depressive illness. This lithium neuroprotection could suppress the toxicity of over-dose of carbamazepine, thereby improving its efficacy/toxicity ratio.